U Carcinoma in Situ of the Upper Urinary Tract Diagnostic Ureteroscopy for Cases Clinically Suspected of

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rothelial carcinoma of the upper urinary tract (UTUC) is uncommon, accounting for less than 5% of all urothelial carcinomas (UCs) [1-2]. Standard diagnostic methods for UTUC include upper-tract imaging (CT urography [CTU] is the first-line) and urine cytology [3]. The detection rate of UTUC is satisfactory with high specificity for CT urography in paral- lel with the development of CT devices [4]. Current indications for nephro-ureterectomy with ipsilateral bladder cuff excision include cases of suspected UTUC based on imaging and positive urine cytology. However,

there are minor cases with consistently positive urine cytology that show poorly detectable lesions in the upper urinary tract, i.e., filling defects and/or wall thickness, on imaging studies. Such cases in whom lower urinary tract malignancy has been excluded are suspected of flat UTUC or carcinoma in situ of the upper tract (UT-Cis). However, there is poor evidence of effi- cient diagnostic options for such cases.

Ureteroscopy (URS) for the upper urinary tract was previously a relatively invasive work-up with common adverse effects. Recently, small-diameter, flexible, high-resolution ureteroscopes have enabled safe access

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Original Article

Diagnostic Ureteroscopy for Cases Clinically Suspected of Carcinoma in Situ of the Upper Urinary Tract

Katsumi Sasaki^＊, Koichiro Wada, Motoo Araki, Yasuyuki Kobayashi, Morito Sugimoto, Shin Ebara, Toyohiko Watanabe, and Yasutomo Nasu

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan

We elucidate the fate of cases clinically suspected of carcinoma in situ (Cis) of the upper tract with serial uret- eroscopy. Of 143 patients who underwent ureteroscopy for suspected upper tract urothelial carcinoma (UTUC) between January 2008 and February 2016, 12 cases with consistently positive urine cytology and poorly detect- able upper-tract malignancies by imaging were reviewed. In these 12 patients, 19 ureteroscopy procedures (25 renal units) were performed. Vesical random biopsy was performed before the 1st ureteroscopy to exclude malignancy of the bladder in all 12 cases. Median follow-up was 42 (13-67) months. Positive biopsy results at the 1st ureteroscopy were obtained in 3 (25%) patients and all were diagnosed wth Cis of the upper tract. Two (17%) of 9 patients who were negative or inconclusive at the 1st ureteroscopy were finally diagnosed as UTUC, but plural ureteroscopy procedures were needed for the diagnoses in both. Carcinoma of the bladder appeared in 5 (42%) patients during follow-up, despite the earlier ruling out of vesical malignancy. Four (33%) of those 5 patients never developed upper-tract urothelial carcinoma during follow-up. Caution is required before under- taking radical surgery for cases clinically suspected of Cis of the upper tract. In our experience, only 42% of such patients developed UTUC; another 33% eventually developed carcinoma of the bladder without UTUC.

Key words: carcinoma in situ, carcinoma of the bladder, upper tract urothelial carcinoma, ureteroscopy, urine cytology

Received September 23, 2016 ; accepted January 17, 2017.

＊Corresponding author. Phone : +81-86-235-7287; Fax : +81-86-231-3986

E-mail : [email protected] (K. Sasaki) Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.

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to the upper tract and enable tissue to be obtained easily at biopsy; hence, current URS is a valuable tool for diagnosis of upper-urinary-tract disorders.

We have performed URS for upper-urinary-tract disorders for more than 2 decades, and have reported the usefulness of URS for diagnosing and treating idio- pathic renal bleeding [5], and for detecting small, low- grade upper tract tumors and prescribing nephron-sparing treatment options [6]. In this study, we assess the usefulness of diagnostic URS for cases with consistently positive cytology and upper-urinary-tract lesions that are poorly detectable on imaging. We also report the final diagnoses of these cases during follow-up.

Materials and Methods

After approval from the Okayama University Hospital Institutional review board and an ethics com- mittee review board (No. 1604-505-001), 143 clinical records of patients undergoing URS evaluation for suspected UTUC at our institution between January 2008 and February 2016 were reviewed. Of 143 patients, 12 cases were highlighted as having consistently positive urine cytology (class IV or V on cytological evaluation) and poorly detectable malignant lesions in the upper urinary tract on imaging. The standard imaging method was enhanced CT urography; in patients for

whom iodinated contrast media were contraindicated, MR urography was used instead. Cystoscopy and vesical mucosa random biopsy (including prostatic urethra in men) were performed in all 12 cases before the 1st URS to exclude malignancy of the bladder.

URS procedures at our institution are as follows.

Under general anesthesia, ureteral orifice and lower ureter are first observed using a rigid ureteroscope (Fibre Uretero-Renoscope, Richard-Wolf, Knittlingen, Germany). The middle and upper ureter and pelvis are observed next using a flexible ureteroscope (URF-P5, URF-P6, Olympus, Tokyo, Japan). If clinicians detect lesions suspected of malignancy—i.e. irregular, edem- atous, reddish mucosa—a biopsy is performed with 3-Fr biopsy cup forceps (Cook Japan, Tokyo, Japan).

Three tissue samples are usually obtained at biopsy.

We evaluated whether diagnostic URS could detect UTUC that imaging studies could not detect decisively.

We also evaluated the final diagnoses of the 12 patients examined.

Results

Median follow-up was 42 (13-67) months. Patient backgrounds of the 12 cases are summarized in Table 1.

Six of the 12 patients had a previous history of bladder cancer (Cis; 3 patients, Non-Cis; 3 patients). The 1st URS was performed after excluding present malignancy

Table 1　 Patient characteristics, urine cytology, imaging ﬁndings and ﬁnal diagnosis Pt. No. Sex Age Urine cytology

before URS Imaging before

URS Previous history of

Bladder cancer Final diagnosis

1 Male 73 V CT none UTUC (non-Cis)

2 Male 70 V CT none Cis of the bladder

3 Female 77 V CT non-Cis UC of the bladder (non-Cis)

4 Female 63 V CT Cis no malignancy (followed up)

5 Male 69 V CT non-Cis Cis of the bladder

6 Male 69 V CT Cis UT-Cis

7 Female 61 IV CT, MRI none Cis of the bladder→UTUC (non-Cis)

8 Female 75 V CT Cis UT-Cis

9 Male 43 IV CT none no malignancy (followed up)

10 Female 62 V CT none no malignancy (followed up)

11 Female 53 V CT non-Cis Cis of the bladder

12 Male 66 V CT, MRI non UT-Cis

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of the bladder in each of the 12 patients. Three cases of UT-Cis were diagnosed histologically at the 1st URS.

Two of these 3 UT-Cis cases diagnosed at the 1st URS had a previous history of Cis of the bladder. Two of the 9 patients who were not diagnosed with UTUC histologically at the 1st URS were considered to be clinical UT-Cis, and received intrarenal Bacillus Calmette- Guerin (BCG) therapy. In one patient the positive urine cytology disappeared, and this patient was followed up.

Another patient showed a consistently positive cytology and a 2nd URS was considered. Another 7 of the 9 patients who were not diagnosed with UTUC histologically at the 1st URS were followed up; in 2 of these 7 patients, positive urine cytology disappeared but follow-up was continued. Another 3 of the 7 patients showed a new appearance of Cis of the bladder. Another 2 of the 7 patients continued positive cytology and a 2nd URS was considered. Ultimately 3 patients received a 2nd URS and all failed to diagnose UTUC histologically. One of the 3 patients who received a 2nd URS were considered to have clinical UT-Cis, and received intrarenal BCG therapy, but was finally diagnosed with UTUC (non-Cis) in imaging during follow-up.

Another patient, who showed a new appearance of Cis of the bladder during follow-up, received intravesical BCG therapy with Cis disappearing histologically after treatment, but was finally considered for a 3rd URS because of recurrent positive cytology during follow-up.

Another patient continued to show positive cytology and a 3rd URS was considered. Ultimately, 2 patients received a 3rd URS. One of these 2 patients who received a 3rd URS was histologically diagnosed with UTUC (non-cis). Another patient who was not diagnosed with UTUC histologically at the 3rd URS was ultimately diagnosed with bladder cancer (non-Cis) during follow-up. A summary of clinical progress and results are shown in Fig.1.

In summary, a total of 19 URS procedures (25 renal units) were performed in 12 patients with consistently positive cytology and no or poorly detectable upper- urinary-tract lesions on imaging. In these 19 URS procedures, 17 biopsies (17 renal units) were performed.

Of these 12 cases, UT-Cis was histologically diagnosed in 3 patients at 1st URS. Non-cis of the upper tract was ultimately diagnosed in 2 patients, but plural URS procedures were needed for the diagnosis in both. Five patients developed carcinoma of the bladder during follow-up, despite vesical malignancy having been

ruled out by mucosa biopsy. In 2 patients positive urine cytology disappeared after the 1st URS, and follow-up was continued without any symptoms or suspicions signs on imaging.

Discussion

The European Association of Urology (EAU) guide- line on UTUC includes cytological evaluation of urine, cystoscopy to exclude malignancy of the bladder, and imaging as the standard diagnostic work-up [3]. CTU is the standard imaging method, and has replaced intravenous excretory urography. The detection rate of UTUC is satisfactory for CTU, with both high sensitivity and specificity. In addition, the wall thickness of the upper tract on CTU is considered to be a sign of UTUC, even when there is no luminal mass effect. However, sensitivity drops for small or flat lesions even with the latest CTU [7]. Patients who cannot undergo CTU due to contraindication of iodinated contrast media typi- cally undergo MR urography, the detection rate of which is less than that of CTU [8]. The usefulness of diffusion-weighted MR for improving cancer detection has been reported [9]. The diffusion coefficient values of highly malignant tumors have been reported to be lower than those of less malignant tumors. However, diffusion-weighted MR cannot detect UT-Cis, which is a highly malignant tumor. Asai et al. reported an out- standing positive predictive value (PPV) of 95% in diagnoses of UTUC using fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT), a new imaging option [10], but with the limitation that this sensitivity is lower in diabetic patients. PET-CT also cannot detect UT-Cis.

Application of diagnostic URS for evaluating suspected UTUC is controversial, with low-grade evidence supporting either view [3,11]. Some updated reports value URS not only as a diagnostic tool but also as an endoscopic management tool for UTUC, with recent small-diameter, flexible, high-resolution ureteroscopes resulting in satisfactory safety and ease of work-up [12,13]. One report found that the technical success rate of URS in UTUC patients was 95%, and that biopsies using such ureteroscopes could obtain a satisfactory accurate diagnostic tumor grade regardless of sample size [14]. Tsivian et al. reported that routine use of diagnostic URS in the evaluation of suspected UTUC reduced misdiagnoses (non-UC with final pathologic

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Fig. 1　 Summary of clinical progress and results of 12 patients.

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findings) [15]. They also emphasized that URS evaluation appeared to increase other nephron-sparing treatment options. However, these reports do not mention the type of UTUC, nor the definition of suspected UTUC (suspected with imaging study or urine cytology).

We have adopted routine URS in the evaluation of suspected UTUC, and have reported the possibility of cancer control for nephron-sparing treatment options under URS [16]. In the present report, we focus on cases with consistently positive cytology and upper- urinary-tract lesions poorly detectable by imaging such as CTU, and evaluated the usefulness of diagnostic URS for such cases. Cis of the upper tract was diagnosed histologically in only 3 of the 12 patients, but all 3 cases were diagnosed at the 1st URS. Two of these 3 UT-Cis cases had a previous history of Cis of the bladder. These results indicate that URS is useful and should be strongly considered for detecting UT-Cis in patients with a previous history of Cis of the bladder.

Another finding from our present data is that carcinoma of the bladder ultimately appeared in more than 40% of the patients during follow-up, regardless of vesical malignancy having been ruled out before URS.

These cases must have had a very small area of carcinoma that could not be detected with a random vesical mucosa biopsy but produced the consistently positive cytology and were finally diagnosed as bladder cancer.

The number of patients with carcinoma of the bladder was greater than that of patients with UT-Cis. Benign pathologic results were detected when these patients underwent radical nephro-ureterectomy. Indeed, Hong et al. report the incidence of benign results after laparo- scopic radical nephro-ureterectomy with preoperative suspicion of UTUC, and indicate the need for careful and thorough preoperative counseling [16]. Our small sample of data may suggest that radical nephro-ureterectomy requires caution, and that frequent follow-up with urine cytology and imaging studies, and/or possible URS, should be considered for cases clinically suspected of UT-Cis due to consistently positive cytology and upper-urinary-tract lesions poorly detectable by imaging.

One concern from our data is that in 2 of 12 patients in whom URS did not detect UC lesions, positive urine cytology disappeared after URS. Reports that the PPV of urine cytology for UTUC is generally very high [17], and that identification of UT-Cis lesions under URS is

not satisfactory [12] suggest that these 2 patients would need strict follow-up.

The findings of this study have some limitations.

First, the retrospective nature of the study must be taken into account. Second, the 12 patients evaluated in the study include those with a past history of bladder cancer, although the random biopsy of vesical mucosa ruled out malignancy of the bladder prior to URS. In addition, we did not evaluate upper tract selective cytology (UTC) because catheterization for collecting urine samples from the upper tract could produce mis- leading results. Namely, catheterization can affect the cellularity and nuclear morphology of a urine sample [18]. The procedure may also affect the morphology of the upper tract mucosa, making the mucosa mimic Cis.

Finally, the small sample size prevents us from reaching statistical conclusions. Our results need to be con- firmed with well-designed observational studies.

URS was performed only under white light (WL) in this study. Recent developments in optical diagnostics have been reported to improve the diagnostic accuracy of UTUC [19]. Traxer et al. report that the URS tumor detection rate was improved by 22.7% using narrow- band imaging (NBI) technology, and that in 27 patients, 5 additional tumors that were considered normal under WL could be detected under NBI, suggesting the usefulness of the technology for detecting UTUC by URS [20]. We should also consider routine URS using these new optical diagnostics technologies, although evidence of daily clinical use is still insufficient.

The present study concluded that radical surgery should be approached with caution, and frequent follow-up with urine cytology and imaging studies, and/or possible URS, should be considered in cases in whom UT-Cis is suspected due to consistently positive cytology and upper-urinary-tract lesions that are poorly detectable by imaging. Biopsy under URS should be strongly considered for cases with a previous history of Cis of the bladder.

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